Viruses from the human herpesvirus family are estimated to infect 90% of the adult population worldwide and are responsible for lifelong debilitating and congenital infections. Some members of this family are associated with human cancers and age-related cognitive decline. Herpes simplex virus (HSV1) has infected more than 3.7 billion people under the age of 50 (67% of the population). HSV1/2 causes significant disease during acute infection (oral and genital lesions, corneal blindness and encephalitis) and establishes persistent latent infections in sensory neurons for the life of the host with the potential for reactivation and recurrent disease. In the US, the economic burden of HSV infection due to social and medical concerns is estimated at over $400 million each year. Other members of the herpesvirus family are associated with even more severe disease states especially in immunocompromised individuals. Although much of the impact of herpesvirus pathogenesis can be controlled by drug therapy, the emergence of drug resistance has threatened these treatment efforts. We have formed a new start up venture, Quercus Molecular Design (QMD LLC) whose long-term objective is to identify, characterize, and exploit multiple drug targets of human herpesviruses. QMD will leverage decades of HSV genetic and biochemical research from Dr. Sandra Weller's laboratory with Dr. Dennis Wright's expertise in small molecule drug discovery and development in infectious disease. Existing strategies for development of new herpesvirus therapies have focused on individual viral targets such as the viral polymerase. QMD is focused on developing novel therapeutic agents for HSV by pursuing multi-targeting inhibitors that block two or more essential viral proteins that fall into the nucleotidyltransferase superfamily (NTS). This approach is expected to lead to the production of antivirals that are less susceptible to the development of mutation-based resistance. HSV encodes three essential NTS proteins that are characterized by the presence of an acidic catalytic triad: viral single strand DNA binding protein (ICP8), viral terminase (UL15) and viral alkaline nuclease (UL12). Small molecule inhibitors that bind at this site are hypothesized to exhibit potent inhibition of at least two of the proteins, thereby drastically limiting the onset of resistance. In Aim 1 we will prepare lead-like, dual metal-directed chemotypes as multi-target inhibitors of HSV proteins. In Aim 2 we will test lead compounds for efficacy in biochemical assays for ICP8, UL12 and UL15 activity and for reduction of virus production. We anticipate the identification of multiple lead scaffolds that target two or more of the enumerated viral targets and exhibit antiviral activity. Upon completion of the work in this phase I application, we will be well positioned to pursue further development of novel antiviral agents for treatment of HSV infections.